Inorganic bone adhesion agent and its use in human hard tissue repair

ABSTRACT

The present invention discloses an inorganic bone adhesive and its use in human hard tissue repairs. The inorganic bone adhesive comprises basic compound, phosphate, calcium phosphate bone cement and retarder with the characteristics of rapid hydration rate and high early strength. Inorganic Bone adhesive can be widely used in the artificial joints fixation, screw fixation as well as comminuted fracture fixation. It is a kind of safe and effective adhesive material and beneficial for the fast postoperative recovery. The final hydration reaction products contains the composition of magnesium phosphate, bio-mineral containing ammonium and apatite-like materials, which has excellent biocompatibility and can be gradually absorbed by surrounding tissues after being implanted in vivo, which benefits the in-growth of the new bone.

FIELD OF THE INVENTION

[0001] The invention belongs to the field of the biomedical materials,relating to a kind of novel inorganic bone adhesive for human hardtissue repairs, especially involving in the description and use of theinorganic bone adhesive containing phosphates.

BACKGROUND OF THE INVENTION

[0002] Fracture by trauma is the common disease in orthopaedics, and thetreatment of the unstable fracture (comminuted fracture) is alongstanding problem for the surgeons. At present, the methods ofincision restoration with internal fixation have been widely adopted inclinics home and abroad, and the main of which include micro-platesscrew fixation, intramedullary fixation, tension wire fixation,introosseous wire suture fixation, intraosseous nylon suture fixation,traditional intersection Kernig needle fixation and absorbable polymericscrew fixation, and so on. These methods have different flaws, whichaffect the therapeutic effect and functional restoration of thepatients. For example, since all of the internal fixation materials areforeign ones, the foreign reactions inevitably occur with differentextents. So the second operation is unavoidable in order to take theinternal fixation materials out, which certainly brings the patientextra pain and economic burden. The large area of the wound affects thehealing of the bone. The operation is a troublesome process with highdegree of difficulty. Moreover, the biocompatibility of the implantedmaterials is bad and the fixed strength is low, especially in the spongybone areas.

[0003] In order to overcome the shortcomings of internal fixation and tosolve the problems on the fixation of the small blocks of comminutedfractures, the methods taken in clinics nowadays include the follows:

[0004] 1. Polymethylmethacrylate (PMMA) Bone Cement

[0005] Polymethylmethacrylate (PMMA) bone cement is composed ofmethylmethacrylate, initiator and some filling materials. The freeradical polymerization occurs following the addition of monomer liquidin powder until turning into hard solid. Before setting, the paste canbe easily molded and show adhesion. It is usually used for the fixationof artificial joint prosthesis and that of some comminuted fracture(Kerong Dai, Bone and Joint Injuries Magazine, 1995, 10(4): 210-212).But the strong exothermic behavior in the setting reaction will causethe peripheral tissues necrosis. As the main components of organicglasses, PMMA is aged, loosing and falling apart after a long timeimplantation due to its bad biocompatibility. Its monomer is poisonousand has stimulating smell, which can bring the blood pressure of thepatients lower suddenly and even result in the sudden death. When it isused as adhesion, the ratio of long-dated loose and revision ofprosthesis is relatively high. The non-degradation characteristic of thematerials will keep the fracture from healing and growing for comminutedfracture. In general, the effect of the fixation in comminuted fractureis not very ideal due to the defects of the material itself.

[0006] 2. For comminuted fracture, fracture reduction is usuallyadopted, followed by microplates screw fixation (Prevel et al,J-Hand-Surg-Am, 1995; 20(1): 44-49) or intramedullary fixation (Gonzalezet al, Clin-orthop, 1996, 327:47-54), which is effective for the massivebone fracture. It is much difficult to the fixation of the small blocksof bone fracture. In spongy bone areas, moreover, the screw fixationmethod still has the disadvantage of weak strength, even for the massivebone fracture. The postoperative slippage occurs frequently, whichaffects the postoperative effects and makes the secondary operationnecessary.

[0007] Some absorbable internal fixation materials have been developedto eliminate the secondary operation, such as polycaprolactone (Lowry K.J et al., J. Biomed Mater. Res., 1997 36(4): 536-541), and calciumphosphate glass fibre enhanced poly-lactic acid (Slivka M. A et al., J.Biomed. Mater. Res., 36(4): 469-477). But the rapid decline in theirmechanical strength limits their applications.

[0008] 3. For screw fixation, the slippage usually occurs due to theincompact combination between the screw and the spongy bone. The polymerbone cement, such as PMMA, is used to perfuse the bore surrounding thescrew in clinics and the screw is fixed after the setting of the cement.Consequently, the fixation strength is enhanced. But it becomes looseand falls apart eventually due to the bad biocompatibility andnon-degradation characters of PMMA itself.

[0009] 4. At present, PMMA is used popularly in the joint fixation andfilling of defects after the revision of the prosthesis. (Kuhn K D. Etal, bone cements, Berlin: Springer-Verlag; 2000). Although someimprovements on PMMA have been made including the decrease of its heatliberation, the increase of fluidity and injection capacity, somedisadvantages still exist, like bad biocompatibility, long-term sheddingand higher revision ratios.

[0010] For the fixation of the fracture, screw and prosthesis of thejoints, all available materials and methods exist disadvantages withdifferent extents. It is desirable to improve their properties,especially biocompatibility, exothermicity and fixation strength.

[0011] The magnesium phosphate cement (MPC) is popularly used in therush repair of the airfield and road, owing to the rapid setting andhigh early strength characteristics (WO 9721639 AI, 1997). Weill et al.,disclosed a kind of calcium phosphate bone cement containing magnesiumoxide, soluble phosphate, sand and fly ash, which is used in the rushrepairs in constructions (US 4756762). Sechra disclosed a fast settingcement used in concrete pavements repairs (Cement Concrete Research1993, 23: 254-66). All of these have no special requirements to thecomponents and purities of the raw materials, hydration reaction heat,and the toxicity of the materials and additives.

[0012] Hirano et al., disclosed the calcium-containing magnesiumphosphate cement with the component of Ca₃Mg₃(PO₄)₄ and eugenolsolvents, which is used for the root canal filling and repair (JP04352706, 1992). The results indicated that the cement was non-toxicwith good biocompatibility. But its hardening process was slow and lastsabout 40 min. In particular, the early strength is not high.

[0013] Frazier D. D et al, disclosed a kind of poly (propyleneglycol-fumarate) bone cement reinforced by particles of calciumcarbonate or calcium phosphate. Its early adhesive strength can up to 30MPa, and its highest compressive strength can reach 300 MPa (J. Biomed.Mater. Res., 1997, 35(3): 383-389). Sakai T. et al., disclosed4-META/MMA-TBB bone cement filled with hydroxyapatite (HAP) (J. Biomed.Mater. Res., 2000, 52(1): 24-29), which indicated that the incorporationof HAP was beneficial for the post-stability of the cement and bonefixation. But the compressive strengths of these two kinds of cementswere derived from the polymerization of monomers, rather than thehydration of the inorganic component. Moreover, the materials can't beabsorbed after being implanted in vivo, and the foreign materials existall along. In addition, the heat liberation from polymerization processwill bum the peripheral tissues.

SUMMARY OF THE INVENTION

[0014] An object of the present invention is to disclose a kind ofinorganic bone adhesive with the characteristics of rapid-setting andhigh early strength. Through the hydration reaction of calcium phosphateor magnesium phosphate bone cement, not by free radical polymerization,the paste turned into the hardening body with certain strength andexcellent biocompatibility, which is used in the fixation of thefracture, the fixation and revision of the artificial joint and thereinforcing fixation of the screw. Comparing with PMMA, it can bedegraded and be absorbed gradually, which solves the related problems inoperations and is beneficial for recovery.

[0015] Another object of the present invention is to provide theintroduction and application of inorganic bone adhesive in human hardtissues repairs.

DESIGN OF THE INVENTION

[0016] 1. The hardening body was formed from paste, based on the rapidhydration reaction between magnesia and phosphate. The excellentplasticity and viscosity before hardening contribute to the fixation ofthe artificial joints, the screws and the fragment bones. Its finalfixation strength is dependant upon the strength of the hardening body,the binding strength between the hardening body and the host bone, andthat between the hardening body and the joint bolt. Since the reactionis exothermic, it is necessary to control the reaction rate thereforethe temperature rise can't exceed 50° C. Enhancing the early strengthrequires the increase of the reaction rate as far as possible; however,restraining the temperature over the hydration needs the decrease of thereaction rate. Thus the use of retarder in the present invention issuggested.

[0017] 2. Based on the similar characteristics of the paste transformingto the hardening body under the similar hydration reaction, the earlyhydration reaction rate of calcium phosphate cement (CPC) should beimproved, therefore it can be used in the treatment of the comminutedfracture.

[0018] 3. Temperature has an obvious influence on the setting rate ofcalcium phosphate bone cement, but the setting reaction itself isslightly exothermic. With the characteristics of rapid setting, highearly compressive strength and exothermic setting process, theexothermic rate of MPC can be adjusted by the hydration activity of themagnesium compound. The incorporation of the MPC into CPC can acceleratethe setting of the CPC. The slight expansion of the MPC hardening bodyduring the setting process just makes up the shrinkages of the CPC atthat time, which makes the CPC combine closely with the pore wall. Thiscan be used for the fixation of the fracture and artificial joints.

[0019] The hydration product of magnesium phosphate bone cement isammonium magnesium phosphate; a kind of bio-mineral, and the hydrationproduct of calcium phosphate cement is hydroxyapatite. So the presentinvention has taken the requirements of the high biocompatibility intoconsideration at the initial design.

DETAILED DESCRIPTION OF THE INVENTION

[0020] The mixture of the present invention consists of basic compound,phosphate, retarder and calcium phosphate bone cement.

[0021] The basic compound should generally comprise from about 30 to 80weight percent with the range of about 55 to 65 percent being morepreferred.

[0022] The phosphate may generally comprise from about 20 to 70 weightpercent with the range of about 35 to 45 percent being more preferred.

[0023] The retarder may be utilized from about 0.05 to 10 weight percentby weight of basic compound and phosphate. Preferably an amount from 2to 6 weight percent is utilized.

[0024] The amount of calcium phosphate bone cement may comprise fromabout 0.5 to 20 weight percent by weight of basic compound andphosphate.

[0025] The basic compound is magnesium oxide and/or calcium oxide, ofwhich magnesium oxide is preferred.

[0026] The phosphates are dihydrogen phosphate, including ammoniumdihydrogen phosphate, monocalcium phosphate monohydrate or monocalciumphosphate anhydrous, ammonium polyphosphate, and the mixtures derivedfrom them, of which ammonium polyphosphate and ammonium dihydrogenphosphate are preferred.

[0027] The retarders are sodium chloride, sodium fluosilicate, sodiumpolyphosphate, borate, boric acid ester and the mixtures derived fromthem, of which sodium borate is preferred.

[0028] CPC is the mixture of several kinds of calcium phosphates and itcan be prepared by the method disclosed in U.S. Pat. No. 5,525,148 andU.S. Pat. No. 5,545,254. It could be the mixture of one or two oftricalcium phosphate (α-type or β-type) and tetracalcium phosphate, andalso could be one or the mixture of octacalcium phosphate, calciumdihydrogen phosphate, hydroxyapatite and fluorapatite.

[0029] Preparation and Application of the Inorganic Bone Adhesive

[0030] Inorganic bone adhesive powder can be obtained by evenly mixingall kinds of raw materials mentioned above according to fixedproportion, of which the basic compound is the dried powder with thediameter range of 1 um˜10 um. The setting liquid is added to make theinorganic bone adhesive powder into paste and it can be implanted intothe body subsequently. The proportion between inorganic bone adhesiveand liquid is from 3:1 to 5:1 (g/ml).

[0031] The setting liquid could be saline, redistilled water or thewater solution of the additives and regulators. The quantity of liquidsis determinated by the standard viscosity measurement method. Since theliquid adopted is different, the-fluidity and viscosity of the paste aredifferent, therefore the hydration rate and the early and final strengthof the hydration are different.

[0032] In order to understand the invention better, the illustration ismade further through the characteristic determination in vitro andbiocompatibility evaluation of inorganic bone adhesive. And the attachedfigures show the experimental results.

[0033] Methods and Experiments

[0034] (1) Setting Measurement

[0035] Inorganic bone adhesive paste (example 1) was loaded into astainless-steel mold (6 mmD×12 mmH) with periodic packing by means ofstainless-steel rod (5.66 mm in diameter). The force applied to the rodpacking was 2 kg to expel air as far as possible. The paste was shapedlike cylinder, then the specimen was removed and put into a glass tube(8 mmD×20 mmH), and then the glass tube was sealed with film and storedat 37° C., 100% relative humidity for some time. Take it out to measurethe compressive strength. The load is exerted at a rate of 1 mm/min on auniversal testing machine. Each group should contain at least 5 paralleltest samples. FIG. 1 indicates that the strength has reached 35 MPa atthe point of 0.5 hour and 70 MPa at the point of 1 hour, respectively.

[0036] (2) Viscosity Strength Measurement

[0037] A. Inorganic bone adhesive paste (example 1) mixed adequately wasloaded into the stainless-steel mold (10 mmD×10 mmH) with periodicpacking by means of stainless-steel rod (5.6 mm in diameter). The forceapplied to the rod packing was 2 kg to expel air as far as possible. Andthen the sample was sealed with film and stored at 37° C., 100% relativehumidity for some time. The viscosity strength was calculated throughthe pressure divided by the contacting area between the material and thestainless steel wall. The load is exerted at a rate of 1 mm/min on auniversal testing machine. Each group should contain at least 3 paralleltest samples.

[0038] B. The bone adjacent the joints was shaped like cylinder anddrilled in the center. The surface of the bone is scrubbed and handled.Inorganic bone adhesive paste (example 1) was loaded into the bonecavity (10 mmD×15.7 mmH), and then the sample was stored at 37° C., 100%relative humidity for some time. The viscosity strength was calculatedthrough the pressure divided by the contacting area between the materialand the surrounding bone. The load is exerted at a rate of 1 mm/min on auniversal testing machine. It can be expressed by the followingequations: $\sigma_{ch} = {\frac{F}{S} = \frac{F}{\pi \cdot D \cdot H}}$

[0039] It is indicated that the viscosity strength between the materialand the stainless steel has reached 2.67 MPa after setting for 0.5 hour.The maximum viscosity strength is 10.99 MPa over the hydration period.

[0040] In order to investigate the viscosity strength between thematerial and the bone, spongy bone from joints was used to measure theviscosity strength between them. The measuring result is 3.95 MPa.According to the bibliographic report (Kerong Dai, et al., China TraumaMagazine, 1989,27(5):309-313), the necessary strength required betweenthe bone cement and the bone interface for the adults with the standardweight is 0.92 MPa, and the viscosity strength between PMMA and bonereaches 2.0 MPa after 24 months (J. Biomed. Mat. Res. 2000, 49(2):237-88). It shows that the above results can meet the requirements inclinical application.

[0041] (3) Adiabatic Measurement

[0042] It was well known that human tissue is sensitive to thetemperature. High temperature probably results in the un-recovereddegeneration of the protein or the death of the bone cell. Even if noinfection, it may cause aseptic necrosis postoperation, which wouldresult in the loose and gap between the tissue and materials.

[0043] Consequently, heat liberation is another importantcharacteristics for the material. Our purpose is to ensure the rapidsetting of the materials, and also to control the exothermicity as faras possible. Just in this way, the heat liberation will do little harmto the peripheral tissues.

[0044] A. Inorganic bone adhesive paste (example 1) mixed adequately wasloaded into a glass tube. Insert the thermometer quickly and make glassbulb containing mercury in the center. The glass tube was put into thethermos bottle filled with glassy-cotton and the temperature wasrecorded at various intervals.

[0045] B. The test was made according to the methods described in“Surgery implants-acrylic acid bone cement, Appendix C: the measurementof the highest exothermic temperature of the system”. The test mold wasshown in FIG. 4 and FIG. 5, which was made of polytetrafluoroethylene.

[0046] The experiment is carried out at 22° C., 80% relative humidity.Inorganic bone adhesive pastes (Example 1 and Example 2) were quicklyloaded into the mold respectively within 1 minute before setting of thematerial. Insert the thermometer quickly and begin to record thetemperature. It was recorded every 30 seconds at the beginning and every5 or 10 minutes when the variation of the temperature is slight. FIG. 6showed that the exothermicity of cement was dependant on the amount ofacidic component in the system. The curve 1 (Example 1) and curve 2(Example 2) represent the specimens setting rapidly and slowly,respectively. With the comparison between two curves, the rapidhydration reaction would lead to the sharper exothermic peak and most ofthe heat is released in a short period and the highest temperature overthe hydration can reach 50.1° C. On the contrary, the slow hydrationreaction of the system would cause the wider exothermic peak and most ofthe heat is released in a relative long period, and the highesttemperature is only 39.8° C. The temperatures are acceptable to humanbeings. The setting time and early strength corresponding to the twocurves are summarized in the Table 1. TABLE 1 The relationship among thesetting time, the early strength and the highest temperature Settingtime/min σ _(0.5 hr)/MPa Highest temperature ° C. Curve 1 8.7 59.86 50.1Curve 2 13.8 31.84 39.8

[0047] (4) Biocompatibility

[0048] As a kind of biomaterial, inorganic bone adhesive wouldinevitably contact with the human tissues and bloods. In order to ensurethe security of the human and prevent the side reaction in clinicalapplication caused by the material after being implanted into the body,it is necessary to make a complete evaluation for the safety of thematerial, the biocompatibility of the material, the adhesion behaviorbetween the material and the bone, the stability of the material afterthe material is implanted into the body.

[0049] (4)-1 Toxicity Experiment

[0050] 25 g of inorganic bone adhesive paste (example 1) were made into1 mm-thick slices. Quality Detection Center for medical polymer productsunder State Food & Drug Administration was entrusted to conduct thecytotoxicity test, skin sensitization test, intracutaneous test, andacute systemic toxicity according to GB/T16175-1996 standard. Theresults are summarized in the table 2. TABLE 2 The results of thetoxicity Items Requirements Results Conclusions Cytotoxicity test ≦1grade Proliferation Qualified method: 0 grade Skin sensitization NoSensitization rate: Qualified test 0% Intracutaneous test No Stimulatingindex: Qualified 0.0 Acute systemic No No Qualified toxicity

[0051] The results indicated that all the tests are qualified and thematerial proves to be non-toxic and would be safe when used into theanimal experiment, which laid a solid foundation for the application ofthe inorganic bone adhesive.

[0052] (4)-2 Implant Experiment

[0053] A. Preparation of the Standard Implanted Specimen

[0054] Inorganic bone adhesive paste (example 1) mixed adequately wasloaded into the stainless steel mold (6 mmD×10 mmH) and the mold (3.2mmD×10 mmH). The force applied was 2 kg to expel air as far as possibleand the specimens were sterilized by Co-60 irradiation before beingimplanted into the body.

[0055] B. Animal Implant Experiment

[0056] 15 rabbits with the weight of 3 kg (provided by Animal Center ofShanghai Secondary Military Medical University) were divided into 5groups and each group contained 3 ones. The rabbits were made lie on theback and then fixed on the plate. 3% pentobarbital was used in theabdominal injection for narcosis at the dosage of 30 mg/kg. 2 ml ofblood was drawn by puncture of vein, and then it was put into thebiochemical glass tube marked in advance. The specimen was in staticculture for more than 0.5 h, and then temporarily stored in 4° C.refrigerator or sent to be tested in time. The hair at calvarium andfront left leg was taken, and then the skin was sterilized by iodine andcovered with sterilized towel. A cut on the left-side calvarium was madeto cause the exposure of the skull. The periosteum was cut open andlateral bone plate was eliminated to form a bone groove (6 mmD×10 mmH).The MPC (6 mmD×10 mmH) specimens were implanted, and then the softtissue was sutured closely in delamination. Antibiotics ointment wasspread on the cut. The proximal part of the front left leg was bondedwith tourniquet. A slitting was made in the outer condyle of the femur.The external condyle was expose and the periosteum was cut open. Theinternal condyle was expose and the periosteum was cut open by using thesame method. A hole was drilled by a 3.2 mm drill in diameter with thehorizontal trend of external condyle to internal condyle. The residueswere cleaned and the bleeding was stopped with wet sponge. The MPC (3.2mmD×10 mmH) specimen was loaded into the bone cavitas and then softtissue was sutured closely in delamination. The tourniquet was unbindedand antibiotics ointment was spread on the cut. 2 ml of blood was drawnpostoperatively for biochemical evaluation. X-ray examination wasimmediately taken postoperatively anteroposterior and lateral,respectively. The rabbits were sent back to the animal house and itslower limbs had no limitation in activities. Each group (3 rabbits) waskilled in 0.5 month, 2 months, 3 months, 6 months, 12 monthspostoperative and the specimens were taken out, respectively. Beforetaking out of the specimens, 3% pentobarbital was used in the abdominalinjection for narcosis at the dosage of 30 mg/kg. 2 ml of blood wasdrawn by puncture of vein for biochemical examination. X-ray examinationwas made on the implanted site. The specimens implanted in skull weretaken out and the photographs were also taken. Biomechanical measurementwas carried out and then XRD analysis was taken. The SEM examination ofthe cross-section was made.

[0057] The specimens in the femur ankle of the front left leg were takenout. The changes in morphology were examined combined with theobservation of the growth of the bone at the interface. The formation offibrous films, the inflammation and necrosis between the implants andsurrounding tissues also should be taken into consideration. Thephotographs of the specimens were taken, and then the specimens weredivided into two parts. One part was put into fixation liquid for themicroscope examination. The other was put into the special fixationliquid for the SEM examination. The histological evaluation was carriedout based on the analysis of the microscopic photographs and SEMmicrograph.

[0058] C. Biochemical Analysis of Blood

[0059] 2 ml of blood was drawn from the veins at the ear edge of therabbit preoperatively and postoperatively, and then used for thebiochemical assays. The concentration of serum calcium, serum phosphatewas determinated by CX-3 automatic biochemical analysis instrument,while the concentration of serum magnesium was analyzed by VIDEO-22atomic spectrophotometer.

[0060] D. Examination of the Degradation for the Specimens

[0061] The specimens implanted in skull were taken out, and then thephotographs of the specimens were taken to examine the degradation forthe implants.

[0062] E. Biomechanics Test

[0063] The specimens implanted in skull were taken out and thecompressive strengths were measured with the loading rate of 1 mm/min ona universal testing machine.

[0064] After inorganic bone adhesive paste (example 1) was implanted for3 months, the concentration of the serum calcium, the serum phosphateand the serum magnesium remain the normal physiological level and haveno apparent differences, except the slight fluctuation in serumphosphate. The results indicated that the implanted material did notcause an obvious change in the animal's metabolism, and the metabolismof the bodies themselves could balance the concentration of the serumcalcium, serum phosphate and serum magnesium.

[0065] The results of the implant experiments indicated that thebiocompatibility of the inorganic bone cement paste (example 1) with thesurrounding tissue was good and it has no obvious foreign body reaction,inflammatory reaction and tissue necrosis after the material wasimplanted into the body. The material can be degraded gradually, whichbenefit for the replacement of the material and growth for the new bone.

BRIEF ILLUSTRATION OF THE FIGURES

[0066] The invention itself, as well as further objects and advantagesthereof, will be better understood with the attached drawings, in which:

[0067]FIG. 1, the variation of the compressive strength with time

[0068]FIG. 2, the mold for the measurement of the viscosity strength

[0069]FIG. 3, the variation of the viscosity strength with time

[0070]FIG. 4, the mold for measurement of calorimetric behavior

[0071]FIG. 5, the diagrams of A-A face of FIG. 4

[0072]FIG. 6, adiabatic curves of the inorganic bone adhesive

EXAMPLE 1

[0073] The dried reactive MgO powder with the diameter less than 10 μmwas mixed with the dried ammonium dihydrogen polyphosphate by the ratioof 1:1 (weight ratio) to form the inorganic bone adhesive powder withthe characteristics of the hydration and adhesion. The powder was thenmixed adequately with the retarder by the ratio of 10:0.05 (weightratio). The powder was then evenly mixed with the saline by the ratio of4.5:1 (weight/volume) to form the slurry, which subsequently wasimplanted into the body.

EXAMPLE 2

[0074] The dried reactive MgO powder with the diameter less than 10 μmwas mixed with the dried ammonium dihydrogen polyphosphate by the ratioof 10:5 (weight ratio) to form the high-active inorganic bone adhesivepowder with the characteristics of the hydration and adhesion. Thepowder was then mixed adequately with the ratio of 10:0.5 (weight ratio)or the retarder could also be dissolved in a liquid at the same ratio.The powder could also be mixed adequately by the ratio of 4:1(weight/volume) with the saline to form the slurry, which subsequentlywas implanted into the body.

EXAMPLE 3-4

[0075] The powder in example 1 or example 2 was mixed with the calciumphosphate bone cement powder by the ration of 10:1 (weight ration) toform the mixed inorganic bone adhesive. The saline was added into thepowder to form the slurry, which subsequently was implanted into thebody.

INDUSTRY PRACTICABILITY

[0076] From the above, the inorganic bone adhesive in the presentinvention is a kind of safe and effective cement and has the followingadvantages.

[0077] (1) With the rapid hydration rate and high early strength, it isbeneficial for the stability of the fixed site. Especially during theoperation, it is favorable for shortening operating time and the fastpostoperative healing.

[0078] (2) The viscosity of the slurry is good, which is helpful for theadhesion and fixation.

[0079] (2) The final hydration products are the bio-minerals andapatite-like, such as ammonium magnesium phosphate. It has nostimulating reaction to the body and is beneficial to maintain thelong-term strength owing to good biocompatibility. It even can beabsorbed by the organism gradually and be useful to the ingrowth of thenew bone.

1. The inorganic bone adhesive comprising: from about 30 to 80 weightpercent of magnesium oxide; from about 20 to 70 weight percent ofphosphate; from about 0.05 to 10 weight percent of retarder by weight ofbasic compound and phosphate; from about 0.5 to 20 weight percent ofcalcium phosphate bone cement by weight of basic compound and phosphate.The basic compound is magnesium oxide and/or calcium oxide. Thephosphates are dihydrogen phosphate. The retarder is selected fromsodium chloride, sodium fluosilicate, polyphosphate sodium, borate,boric acid ester and the mixtures derived from them.
 2. The inorganicbone adhesive of claim 1 wherein said comprising: from 55 to 65 weightpercent of basic compound; from 35 to 45 weight percent of phosphate;from 2 to 6 weight percent of retarder by weight of basic compound andphosphate; from about 0.5 to 20 weight percent of calcium phosphate bonecement by weight of basic compound and phosphate.
 3. The inorganic boneadhesive of claim 1 or claim 2 wherein said basic compound is magnesiumoxide.
 4. The inorganic bone adhesive of claim 1 wherein said phosphateincludes ammonium dihydrogen phosphate, monocalcium phosphatemonohydrate, monocalcium phosphate anhydrous, ammonium polyphosphate,phosphoric acid and the mixtures derived from them.
 5. The inorganicbone adhesive of claim 4 wherein said phosphate is ammoniumpolyphosphate or ammonium dihydrogen phosphate.
 6. The inorganic boneadhesive of claim 1 or claim 2 wherein said retarder is sodium borate.7. The inorganic bone adhesive of claim 1 or claim 2 wherein saidcalcium phosphate bone cement is selected from the group consisting oftricalcium phosphate (α-type or β-type) and tetracalcium phosphate,octacalcium phosphate, calcium dihydrogen phosphate, hydroxyapatite andfluorapatite, and the mixtures derived from them.
 8. The application ofthe inorganic bone adhesive of claim 1, claim 2, claim 4 or claim 5wherein said inorganic bone adhesive is to repair the hard tissues ofhuman or to prepare the materials for human bone defect repairs.
 9. Theapplication of the inorganic bone adhesive of claim 3 wherein saidinorganic bone adhesive is to repair the hard tissues of human or toprepare the materials for human bone defect repairs.
 10. The applicationof the inorganic bone adhesive of claim 7 wherein said inorganic boneadhesive is to repair the hard tissues of human or to prepare thematerials for human bone defect repairs.